The subject matter of each of U.S. application Ser. Nos. 08/528,510, 08/712,881 and 09/199,873 is herein incorported in its entirety by reference. All patents, copending applications and publications referred to herein are, unless noted otherwise, incorporated by reference in their entirety.
The present invention relates to compositions and methods for treatment and/or prevention of hyperalgesic states. The compositions, which are formulated for topical and local administration, contain anti-hyperalgesics that are substantially devoid of central nervous system effects, and, thus, have very little, if any, potential for abuse.
Pain and Analgesia
Pain has been defined in a variety of ways. For example, pain can be defined as the perception by a subject of noxious stimuli that produces a withdrawal reaction by the subject. The most commonly experienced form of pain may be defined as the effect of a stimulus on nerve endings, which results in the transmission of impulses to the cerebrum. This somatic sensation and normal function of pain, referred to as nociception or nociceptive pain, informs the organism of impending tissue damage. Somatic and visceral free nerve endings, termed nociceptors, initially process such pain signals.
Despite numerous definitions, the brain pathways governing the perception of pain are not completely understood. Sensory afferent synaptic connections to the spinal cord, so-called xe2x80x9cnociceptive pathwaysxe2x80x9d, however, have been documented in some detail. The nociceptive pathway, which exists for protection of the organism (such as the pain experienced in response to a burn), is inactive. Activity is initiated by the application of a high intensity, potentially damaging stimulus. This stimulus serves to depolarize certain classes of afferent (sensory) axons of the small unmyelinated category, designed C fibers.
The signal carried by the C fibers travels up the peripheral nerve and into the spinal cord where synapses are made on second order and higher order neurons, which then transmit the pain signal up the spinal cord in the spinothalamic tract ending in the thalamus. Polysynaptic junctions in the dorsal horn of the spinal cord are involved in the relay and modulation of sensations of pain to various regions of the brain, including the periaqueductal grey region. The ventrolateral and ventromedial thalamic nuclei project to the cortex where the pain is then processed with regard to localization and other integrative characteristics.
Opioid Analgesia
Analgesia, or the reduction of pain perception, can be effected directly by decreasing transmission along such nociceptive pathways. Analgesic opiates are thought to act by mimicking the effects of endorphin or enkephalin peptide-containing neurons, which synapse presynaptically at the C-fiber terminal and which, when they fire, inhibit release of substance P from the C-fiber. Descending pathways from the brain are also inhibitory to C-fiber firing. Thus, CNS-mediated analgesia leads to an overall inhibition of the pain transmission.
Agents that selectively block an animal""s response to a strong stimulus without obtunding general behavior or motor function is referred to as an analgesic. Opiates, via interaction with specific receptors in the brain and spinal cord, are able to block the release of transmitters from central terminals (Yaksh et al. (1988) In: Progress in Brain Research, Vol. 77, Chapter 28, Elsevier Science Pub., B. V. pp. 371-94]). They are thus able to increase the intensity of the peripheral stimulus necessary to produce a given pain state. Accordingly, these agents are referred to as analgesics.
Opiate Receptors and Opiate Side Effects
Central opiate receptors (in brain and spinal cord) appear to mediate the effects of systemically administered opiates. Three principal classes of opiate receptors have been identified: xcexc, xcexa and xcex4 (Yaksh, T. L.: Eur. J. Anaesthesiol. 1:201-243, 1984). The use of selective agonists and antagonists have demonstrated that these receptors also appear to mediate peripheral opioid effects. The central and peripheral actions activities of opiates are an important component of their therapeutic utility. It appears that after systemic delivery of opiates such as morphine, the primary effect may be mediated by both sites of action.
On the other hand, many of the principal drawbacks of systemic opiates are the results of their actions within the brain. These actions include sedation, depression of respiration, constipation, nausea and emesis, abuse liability and the development of addiction. These effects serve to limit the utility of opiates for controlling post injury pain. Addiction liability can occur secondary to medical uses of the drug where the central effects lead to an addicted and dependent state.
Because constipation is among the actions of opiates, many agents selected for anti-diarrheal activity act via one or more of these opioid receptors. Also, because of the diverse actions mediated by opioid receptors, such agents also have undesirable central nervous system effects and abuse potential. Because of these diverse activities and the potential for abuse, anti-diarrheal opioid drug development has been directed towards identifying compounds in which the potentially beneficial activities are separated from the activities that lead to abuse and dependence.
During the mid to late 1960""s, several agents derived from classes of molecules known to have opioid activity were synthesized. These agents were shown to have naloxone reversible suppressant effects in smooth muscle bioassays and were able to readily displace opioid ligands in receptor binding assays. These results indicated that they act via direct or indirect action with opioid receptors. These compounds were designed to be selective anti-diarrheal opioid receptor (believed to be the xcexc receptor) agonists that are substantially free from analgesic and habit-forming activities (see, e.q., Shriver et al. (1987) xe2x80x9cLoperamidexe2x80x9d in Pharmacological and Biochemical Properties of Drug Substances, Vol. 3, Goldberg, M. E., ed. Am. Pharm. Assoc., Washington, D.C., p. 462).
Compounds, such as loperamide [4-(p-chlorophenyl)-4-hydroxy-N-N-dimethyl-xcex1,xcex1-diphenyl-1-piperidinebutyramide hydrochloride], and its analogs were among those synthesized. Loperamide was widely reported to be completely devoid of analgesic effects and CNS effects [see, e.g., Jaffe et al. (1980) Clin. Pharmacol. Ther. 80:812-819] even at relatively high dosages. Subsequent work has explored whether loperamide administered to mice intraparenterally might provide analgesic effects [see, e.g., Takasuna et al. (1994) Behavioural Pharm. 5:189-195]. Specifically, Takasuna et al. report that suppression of acetic acid-induced writhing was observed when loperamide was administered. The authors note, however, that the writhing response depends on sensorimotor integration, and that drugs may suppress writhing by impairing the subject""s motoric ability to respond without affecting the sensory events consequent to the administration of a chemical irritant (see, Takasuna et al. (1994) Behavioural Pharm. 5:189-195). The authors state that it remains to be determined whether or not loperamide has any analgesic properties.
In contrast to conventional opiates, however, loperamide and analogs thereof and other such agents exhibit little or no analgesic effects as measured in acute pain models, such as the tail clip and hot plate tail withdrawal tests, when given systemically [see, e.g., Stahl et al. (1977) Eur. J. Pharmacology 46:199-205; Shriver et al. (1981) xe2x80x9cLoperamidexe2x80x9d in Pharmacological and Biochemical Properties of Drug ubstances Vol. 3, Goldenberg, Ed., American Pharmaceutical Assn. Press, pp. 461-476; see, also U.S. Pat. Nos. 3,714,159 and 3,884,916]. This absence of CNS effects, including analgesic effects, is believed to be related to the failure of such compounds to effectively cross the blood brain barrier. This failure is in part due to the extremely high lipid partition coefficient of the compounds. The high partition coefficient results in sequestration of the compound in the lipid membrane. This local absorption is thought to contribute to its failure to cross the blood brain barrier. In support of this conclusion, antinociceptive analgesic action has been observed after direct delivery into the brain [Stahl et al. (1977) Eur. J. Pharmacology 46:199-205].
Peripheral Injury and Hyperalgesia
Changes in the milieu of the peripheral sensory terminal occur secondary to local tissue damage. Mild damage [such as abrasions or burns] and inflammation in the cutaneous receptive fields or joints will produce significant increases in the excitability of polymodal nociceptors [C fibers] and high threshold mechanoreceptors [Handwerker et al. (1991) Proceeding of the VIth World Congress on Pain, Bond et al., eds., Elsevier Science Publishers BV, pp. 59-70; Schaible xc3xa8t al. (1993) Pain 55:5-54]. This increased excitability leads to increased spontaneous activity [in otherwise silent sensory afferents] and an exaggerated response to otherwise minimal stimuli.
These events have several consequences. First, the magnitude of the pain state in humans and animals is proportional to the discharge rate in such sensory afferent [Raja et al. (1988) Anesthesiology 68:571-590]. The facilitated response secondary to the local peripheral injury may lead to an exaggerated pain state simply because of the increased afferent activity. Secondly, spontaneous activity in small sensory afferent causes central neurons in the spinal cord to develop an exaggerated response to subsequent input [Woolf et al. (1991) Pain 44:293-299; Neugebauer et al. (1993) J. Neurosci. 70:1365-1377]. Both of these events, secondary to the increased spontaneous activity and reactivity in small sensory afferents generated by the peripheral injury leads to a behavioral state referred to as hyperalgesia (Yaksh (1993) Current Opinion in Neurology and Neurosurgery 6:250-256).
Thus, in the instance where the pain response is the result of an exaggerated response to a given stimulus, the organism is hyperalgesic. The importance of the hyperalgesic state in the post injury pain state has been repeatedly demonstrated and this facilitated processing appears to account for a major proportion of the post-injury/inflammatory pain state [see, e.q., Woold et al. (1993) Anesthesia and Analgesia 77:362-79; Dubner et al. (1994) In, Textbook of Pain, Melzack et al., eds., Churchill-Livingstone, London, pp. 225-242].
Certain drug actions may serve to normalize the sensitivity of the organism. Experimental investigations have shown that opiates with an action in the vicinity of the peripheral terminal in injured or inflamed tissue will normalize the activity in afferent innervating inflamed skin [Russell et al. (1987) Neurosci. Lett 76:107-112; Andreev et al. (1994) Neurosci. 58:793-798] and normalize the hyperalgesic threshold [Stein (1988) Eur. J. Pharmac. 155:255-264 Stein (1993) Anesth. Analg. 76:182-191]. Opiates, such as morphine, however, when peripherally applied, may have a short duration of action and would, if applied at sufficient levels, have effects upon consciousness and respiration. The possible systemic effects, CNS effects and abuse potential render conventional opioids unsuitable for local application and unsuitable as peripheral anti-hyperalgesics. Thus, there is a need for effective anti-hyperalgesics that directly block peripheral sensitization, but that do not have concomitant central nervous system [CNS] effects, including the potential for abuse.
Therefore, it is an object herein to provide anti-hyperalgesics for local and topical application that have minimal or no CNS effects.
Methods for treatment and/or prevention of peripheral local inflammatory states, including, but not limited to, inflammation following local infection, blister, boils, or acute skin injuries, such as abrasions, burns, such as thermal, radiation, sunburn and chemical burns, windburn, frostbite, superficial cuts, surgical incisions, contusions, irritations, inflammatory skin conditions, including but not limited to poison ivy, and allergic rashes and dermatitis, insect stings and bites, joint inflammation, post-surgical hyperalgesic conditions and any condition that yields a hyperalgesic pain state are provided. Such conditions and indications, include, but are not limited to: a) skin conditions;; b) oral, laryngal and bronchial conditions and indications; c) ophthalmic indications and conditions; d) post surgical conditions and indications; e) recto-anal inflammations; and f) inflammations associated with infectious agents.
These methods involve topical or local administration of compositions that contain one or more compounds that exert anti-hyperalgesic activity via peripheral opiate receptors, but that do not exhibit CNS, CNS-mediated analgesic or systemic effects [particularly CNS effects] at dosages at which they are topically or locally applied. The intended locus of application includes, but is not limited to, any body surface or part that is amenable to local or topical treatment. Such body parts include, but are not limited to: the skin, joints, eyes, lips and mucosal membranes.
The methods use compositions containing opioid anti-diarrheal compounds or other opiate receptor agonist compounds that do not, upon topical or local administration, evoke CNS effects, as defined herein, particularly at the peripheral anti-hyperalgesic dosage. The compositions that contain the opioid anti-diarrheal compounds or other opiate receptor compounds are also provided.
Typically the compounds intended for use in the compositions and methods herein possess peripheral anti-hyperalgesic and substantially no CNS activities, as defined herein, because, without being bound by any theory, they do not effectively cross the blood brain barrier. The failure to cross the blood brain barrier precludes the occurrence of the CNS systemic effects, so that there is limited potential for abuse. Other opioids, such as morphine, that readily cross the blood brain barrier could be effective as anti-hyperalgesics, but their permeability through the blood brain barrier results in abuse liability. Their scheduling by the Drug Enforcement Agency limits their applicability.
In contrast, the compositions provided herein, contain opioids that do not, upon topical or local administration, substantially cross the blood brain barrier as assessed by assays described herein. The compounds intended for use in the methods and compositions provided herein include any compound that by virtue of its interaction, either directly or indirectly, with peripheral opioid receptors ameliorates the peripheral hyperalgesic state, but does not exhibit systemic CNS-mediated analgesic activity [i.e., analgesic activity by virtue of interaction with CNS opioid receptors] or CNS side-effects, including heaviness of the limbs, flush or pale complexion, clogged nasal and sinus passages, dizziness, depression, respiratory depression, sedation and constipation. These compounds include anti-diarrheals that act as anti-diarrheals via interaction with xcexc, xcex4 or xcexa receptors, especially xcexc and xcex4 receptors, and opiate agonists, such as metkephamide and related enkephalin analogs. Examples of such compounds include, but are not limited to:
(i) loperamide [4-(p-chlorophenyl)-4-hydroxy-N-N-dimethyl-xcex1,xcex1-diphenyl-1-piperidinebutyramide hydrochloride]], loperamide analogs and related compounds as defined herein [see, Formula (I); see, also, U.S. Pat. Nos. 3,884,916 and 3,714,159; see, also U.S. Pat. Nos. 4,194,045, 4,116,963, 4,072,686, 4,069,223, 4,066,654,], N-oxides of loperamide and analogs, metabolites and prodrugs thereof and related compounds as defined herein [see, also, U.S. Pat. No. 4,824,853], and related compounds, such as (a), (b) and (c) as follows:
(a) 4-(aroylamino)piperidine-butanamide derivatives and N-oxides thereof as defined herein [see, also U.S. Pat. No. 4,990,521];
(b) 5-(1,1-diphenyl-3-(5- or 6-hydroxy-2-azabicyclo-(2.2.2)oct-2-yl)propyl)-2-alkyl-1,3,4-oxadiazoles, 5-(1,1-diphenyl-4-(cyclic amino)but-2-trans-en-1-yl)-2-alkyl-1,3,4-oxadiazoles, 2-[5-(cyclic amino)-ethyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl]-5-alkyl-1,3,4-oxadiazoles] and related compounds [see, U.S. Pat. Nos. 4,013,668, 3,996,214 and 4,012,393];
(c) 2-substituted-1-azabicyclo[2,2,2]octanes [see, U.S. Pat. No. 4,125,531];
(ii) 3-hydroxy-7-oxomorphinans and 3-hydroxy-7-oxoisomorphinans [see, e.g., U.S. Pat. No. 4,277,605] including, but not limited to: 3-hydroxy-7-oxomorphinan and 3-hydroxy-7-oxoisomorphinans including d,l-3-hydroxy-7-oxo-N-methylmorphinan, l-3-hydroxy-7-oxo-N-methyl-morphinan, d,l-3-hydroxy-7-oxomorphinan, l-3-hydroxy-7-oxomorphinan, d,l-3-hydroxy-7-oxo-N-methylisomorphinan, l-3-hydroxy-7-oxo-N-methylisomorphinan, d,l-3-hydroxy-7-oxoisomorphinan and l-3-hydroxy-7-oxoisomorphinan;
(iii) amidinoureas as provided herein [see, also U.S. Pat. Nos. 4,326,075, 4,326,074, 4,203,920, 4,060,635, 4,115,564, 4,025,652] and 2-[(aminophenyl and amidophenyl)amino]-1-azacycloalkanes [see, U.S. Pat. No. 4,533,739];
(iv) metkephamid [H-L-Tyr-D-Ala-Gly-L-Phe-N(Me)Met-NH2; see, e.g., U.S. Pat. No. 4,430,327; Burkhart et al. (1982) Peptides 3:869-871; Frederickson et al. (1991) Science 211:603-605] and other synthetic opioid peptides, such as H-Tyr-D-Nva-Phe-Orn-NH2, H-Tyr-D-Nle-Phe-Orn-NH2, H-Tyr-D-Arg-Phe-A2bu-NH2, H-Tyr-D-Arg-Phe-Lys-NH2, and H-Lys-Tyr-D-Arg-Phe-Lys-NH2 [see, U.S. Pat. No. 5,312,899; see, also Gesellchen et al. (1981) Pept.: Synth., Struct., Funct., Proc. Am. Pept. Symp., 7th,; Rich et al. (Eds), Pierce Chem. Co., Rockford, Ill., pp. 621-62] that do not cross the blood brain barrier;
(v) propanamines as defined in U.S. Pat. No. 5,236,947; and
(vi) other opioid compounds that may agonize peripheral xcexc or xcexa receptors, especially xcexc receptors, but that, upon topical or local administration, do not cross the blood brain barrier and do not exhibit substantial CNS effects as defined herein.
The methods will employ compounds, such as those listed above, and further include compounds, such as: (viii) certain phenylacetamide derivatives [see, U.S. Pat. No. 5,242,944], including, but not limited to N-{(3,4-dimethylphenyl)propyl}-4-(2-aminoethoxy)-3-methoxy-phenylacetamide, N-{(3,4-dimethylphenyl)propyl}-4-(2-aminoethoxy)-3-hydroxy-phenylacetamide, N-{(3,4-dimethylphenyl)propyl}-4-(2-aminoethoxy)-3-aminophenylacetamide, N-{(3-methylphenyl)propyl}-4-(2-aminoethoxy)-3-methoxy-phenylacetamide, N-{(3-methylphenyl)propyl}-4-(2-aminoethoxy)-3-hydroxy-phenylacetamide and N-{(3-dimethylphenyl)propyl}-4-(2-aminoethoxy)-3-amino phenylacetamide.
Preferred compounds for use in the compositions and methods herein are the loperamide analogs and N-oxides, preferably an N-oxide of a piperidine-nitrogen, thereof or other pharmaceutically acceptable derivatives thereof and related compounds [see (i), above]. These preferred compounds include compounds of formula (I): 
in which:
m is an integer from 0 to 3, preferably 1 to 3, more preferably 1 or 2 , and most preferably 2; 
xe2x80x83is an azabicycloalkyl containing from 6 to 9 carbon atoms with at least 5 atoms in each ring, which ring is preferably pyrrolidino, piperidino, or hexamethylenimino, where the tertiary amine is: 
xe2x80x83and is unsubstituted or substituted with OR18 in which R18 is hydrogen or lower alkanoyl containing 2 to 7, preferably 2 or 3, carbon atoms, and OR18 is preferably attached at the 5 position in 5-membered rings or the 5 or 6 position in 6-membered rings and is attached in the endo or exo configuration, where R3, R7, R5 and R6 are as defined below. The tertiary amine is preferably: 
M is more preferably selected from among: 
xe2x80x83where
m is an integer from 1 to 3, preferably 1 or 2, more preferably 2; and
X1, X2 and X3 are xe2x80x94C(R24)(R25)xe2x80x94, xe2x80x94C(R24)xe2x95x90C(R25)xe2x80x94, xe2x80x94C(R24)xe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90C(R24)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94N(R24)xe2x80x94, with the proviso that only one of X1, X2 and X3 may be O, S or NR24; and
R24 and R25 are hydrogen or lower alkyl.
Ar1 and Ar2 are either (i) or (ii) as follows:
(i) each is independently selected from a ring system, preferably a 6- to 10-membered ring system, more preferably an aryl ring system, or a heteroatom-containg ring system, preferably a 5- to 10-membered heteroatom-containing ring system, more preferably a heteraryl ring system, containing 1 or more heteroatoms, preferably 1 to 3 heteroatoms, such as oxygen, sulfur or nitrogen atoms, wherein the aryl and heteroaryl ring systems are each optionally substituted with one or more, preferably up to three, aryl group substituents [as defined herein], and Ar1 and Ar2 are each preferably independently phenyl or pyridyl, optionally substituted with halo, hydroxy, haloalkyl, preferably halo lower alkyl, particularly trifluoromethyl, alkyl, alkyloxy, aminosulfonyl, alkylcarbonyl, nitro, amino, aminocarbonyl, phenylcarbonyl which is optionally substituted with one or more, preferably up to three, substituents selected from halo, halo alkyl and alkyl, or thienyl which is optionally substituted with halo, haloalkyl or alkyl, where the alkyl groups are straight or branched chain and preferably contain from 1 to 6 carbons, more preferably 1 to 3 carbons; or
(ii) Ar1 and Ar2 are each independently phenyl or pyridyl groups, which are unsubstituted or substituted with, preferably aryl substituent groups, as defined herein, preferably phenyl, and with the carbon to which they are commonly linked form a fused ring system, so that the compounds of formula (I) have the structure: 
xe2x80x83and is preferably, 
xe2x80x83where:
A and B are independently selected from phenyl and pyridyl, preferably phenyl, which are unsubstituted or substituted, preferably with up to three aryl group substituents;
X4 is a direct bond, xe2x80x94(CH2)nxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHCH2xe2x80x94, xe2x80x94(CH2)pO(CH2)qxe2x80x94, xe2x80x94CH2)pS(O)r(CH2)qxe2x80x94, xe2x80x94(CH2)pNR21(CH2)qxe2x80x94 or 
n is an integer from 0 to 3, preferably 1 to 3, and more preferably 2 or 3;
each of p and q is 0 or 1, and the sum of p and q is no greater than 2;
r is 0 to 2;
R2 is a direct bond, is alkylene in which the alkylene group is a straight or branched chain, preferably is alkylene containing from 1 to 12, preferably 1 to 6, more preferably 1 to 3 carbons and most preferably is xe2x80x94(CH2)2xe2x80x94 or xe2x80x94CH2CH(CH3)xe2x80x94, is alkenylene having 2 to 6 carbon atoms, preferably 2 to 3 carbons atoms, and one or two, preferably one, double bond, or is alkynylene in which the alkynylene group is a straight or branched chain, preferably is alkynylene containing from 2 to 12, preferably 2 to 6, more preferably 2 to 3 carbons; in all instances the chains are unsubstituted or substituted, and, if substituted, preferably with one or more hydroxy groups;
R3 is selected from Ar3, xe2x80x94Yxe2x80x94Ar3, where Y is alkylene or alkenylene having, preferably, 2 to 4 carbon atoms; alkenyl containing 2 to 4 carbons; cycloalkyl containing 3 to 8 carbons; heterocycle, preferably 1-pyrrolidinyl, 1-piperidinyl, 1-hexamethyleneiminyl, 1-morpholinyl or xe2x80x94N(Ar4)xe2x80x94R23, where R23 is alkyl; alkenyl; alkanoyl which is optionally substituted, preferably with halo, hydroxy or alkoxy, preferably lower alkanoyl; alkenoyl having 3 to 10 carbons and 1 to 3 double bonds; optionally substituted aroyl, preferably benzoyl; heteroaroyl, preferably pyridoyl, furoyl and thienoyl; alkoxycarbonyl, preferably lower alkoxycarbonyl; alkenyloxycarbonyl having 3 to 10 carbons and 1 to 3 double bonds; aryloxycarbonyl, preferably phenoxycarbonyl; formyl (xe2x80x94CHO); cyano; aminocarbonyl (xe2x80x94CONH2); alkylaminocarbonyl; dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl or arylalkylaminocarbonyl; or 
R8 is hydrogen or alkyl that is a straight or branched chain, preferably containing from 1 to 6, more preferably 1 to 3, carbon atoms;
Ar3 is selected from a ring system, preferably a 6- to 10-membered ring system, more preferably an aryl ring sytem, or a heteroatom-containg ring system, preferably a 5- to 10-membered heteroatom-containing ring system, more preferably a heteraryl ring system, containing 1 or more heteroatoms, preferably 1 to 3 heteroatoms, such as oxygen, sulfur or nitrogen atoms, wherein the aryl and heteroaryl ring systems are each optionally substituted with one or more, preferably up to three, aryl group substituents [as defined herein]; it is more preferably an aryl ring system, preferably a 6- to 10-membered aryl ring system, or a heteroaryl ring system, preferably a 5- to 10-membered heteroaryl ring system, containing 1 or more heteroatoms, preferably 1 to 3 heteroatoms, such as oxygen, sulfur or nitrogen atoms, in which the aryl and heteroaryl ring systems are each unsubtituted or substituted with one or more, preferably up to three, substitutents, preferably aryl group substituents halo, halo lower alkyl or lower alkyl, and Ar3 is preferably phenyl or pyridyl unsubstituted or substituted with halo, halo lower alkyl or lower alkyl;
Ar4 is either:
(i) heterocycle containing 1 ring or 2 or more fused rings, preferably 1 ring or 2 to 3 fused rings, where each ring contains 1 or more, preferably 1 to 3 heteroatoms, and preferably contains 4 to 10 members, more preferably 5 to 7 members, and is optionally substituted with one or more, preferably up to three, aryl group substituents, preferably halo, halo lower alkyl or lower alkyl, and Ar4 is preferably selected from heterocycles that include, but are not limited to, indolyl, benzofuranyl, benzothienyl, isoquinolinyl, quinolinyl, benzimidazoly, thienyl, furanyl, pyridinyl, thiazolyl and imidazolyl, each of which is optionally substituted, preferably with halo, halo lower alkyl or lower alkyl, preferably halo, and the heterocycle is more preferably selected from thienyl, furanyl, pyridinyl, thiazolyl and imidazolyl; or
(ii) a radical of formula: 
xe2x80x83in which:
R10, R11 and R12 are each independently selected from hydrogen, alkyloxy, alkoxyalkyl, halo, hydroxy, cyano, nitro, amino, alkylamino, di(alkyl)amino, aminocarbonyl, arylcarbonylamino, alkylcarbonylamino, alkylcarbonyl, alkylcarbonyloxy, aminosulfonyl, alkylsulfinyl, alkylsulfonyl, alkylthio, mercapto, C3-6alkenyloxy, C3-6alkynyloxy, arylalkyloxy, aryloxy and alkyl, in which alkyl, alkenyl, alkynyl or aryl group defined by R10, R11 and R12 is unsubstituted or substituted with one or more, preferably 1 to 4 substituents selected from halo, halo alkyl, preferably halo lower alkyl, or alkyl, preferably lower alkyl, and the alkyl groups are straight or branched chains that are preferably lower alkyl (C1-6) and more preferably C1-3 or
(iii) 1- or 2-naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl or dihydroindenyl, each of which is optionally substitituted with one or more aryl group substituents;
R is halo, haloalkyl, preferably lower halo alkyl, or alkenyl having 3 to 12 carbons, preferably lower alkenyl or hydroxy and is preferably at the 3-position [relative to the N], more preferably a 3-halo or 3-lower alkyl, or R is OR9 that is preferably at the 3-position so that the piperidinyl ring has the formula: 
R9 is selected from hydrogen, alkyl, arylalkyl, alkylcarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, in which the alkyl groups are straight or branched chains and preferably contain 1 to 12, more preferably 1 to 6 carbons, more preferably 1-3 carbons in the chain;
R4 is selected from among:
(i) an aryl ring system, preferably a 6- to 10-membered aryl ring system, or a heteroaryl ring system, preferably a 5- to 10-membered heteroaryl ring system, containing 1 or more heteroatoms, preferably 1 to 3 heteroatoms, such as oxygen, sulfur or nitrogen atoms, in which the aryl and heteroaryl ring systems are each optionally substituted with one or more, preferably up to three aryl group substituents, and R4 is preferably phenyl or pyridyl which is optionally substituted with lower alkyl, halo or halo lower alkyl, with phenyl being even more preferred, or
(ii) a heterocyclic ring containing one to three heteroatoms, that is unsubstituted or substituted with halo, halo lower alkyl or lower alkyl, and is preferably a pyrrolidinyl, oxadiazolyl or triazolyl radical, more preferably oxadiazolyl, most preferably 1,3,4-oxadiazolyl, particularly a 5-substituted 1,3,4-oxadiazolyl in which the substituent is halo, halo lower alkyl, hydroxy, lower alkoxy or lower alkyl, or
(iii) alkyl containing 1 to 8 carbons which is optionally substituted with hydroxy or alkylcarbonyloxy (xe2x80x94OCOR), preferably 1 to 6 carbons, more preferably 1 to 3 carbons; alkenyl containing 3 to 6 carbons; cycloalkylalkyl in which the cycloalkyl contains 3 to 8 carbons and the alkyl contains 1 to 3 carbons; cycloalkenylalkyl in which the cycloalkenyl contains 3 to 8 carbons and the alkyl contains 1 to 3 carbons; or 
xe2x80x83where
X1 is as previously defined;
X5 is O or S;
R5 and R6 are either:
(a) independently selected from hydrogen, alkyl that is a straight or branched chain containing 1 to 12, preferably 1 to 6 carbons, more preferably 1-3 carbons, alkenyl that is straight or branched chain, containing 2 to 12, preferably containing 3-6 carbons and one or two double bonds, alkynyl that is straight or branched chain, containing 2 to 12, preferably containing 3-6 carbons and one or two double bonds, or aryl, preferably a 6- to 10-membered aryl ring system that is optionally substituted with one or more, preferably up to three, aryl group substituents, or arylalkyl, and each is preferably 2-propenyl, ethyl, methyl or aryl, preferably phenyl or phenylmethyl, or
(b) R5 and R6 are each independently selected from carbon chains, heteroatoms, and carbon chains containing one or more heteroatoms, so that together with the nitrogen atom to which each is attached, they form a 3- to 10-, preferably 4-7, more preferably 5 to 6-membered heterocyclic ring containing one to three heteroatoms, that is preferably a piperidinyl, alkylpiperidinyl, morpholinyl, oxadiazolyl, triazolyl or pyrrolidinyl radical that is unsubstituted or substituted with halo, halo lower alkyl, hydroxy, lower alkoxy or lower alkyl, and is more preferably a 1,3,4-oxadiazolyl, 4-morpholinyl, or di(C1-C6 alkyl)-morpholinyl, preferably 2,6-di(C1-C6 alkyl)-4-morpholinyl, radical;
(v) cyano, formyl, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyl or arylcarbonyl;
(vi) xe2x80x94NR5COR5; or
(vii) xe2x80x94S(O)ralkyl or xe2x80x94S(O)raryl, where r is 1 or 2; and
R7 is selected from among:
xe2x80x94H;
OH;
xe2x80x94R14OR13 in which R13 is hydrogen, lower alkyl, preferably containing 1 to 4 carbons, or alkanoyl containing 2 to 5, preferably 2 or 3, carbon atoms, and R14 is lower alkylene, preferably alkylene of 2 to 4 carbon atoms, more preferably methylene or ethylene, or R14 is alkenylene of 2 to 6 carbon atoms, alkynylene of 2 to 4 carbon atoms;
xe2x80x94CH2NR15R16 in which R15 is hydrogen, lower alkyl, lower alkanoyl, aryl or aroyl, and R16 is hydrogen or lower alkyl or, together with the nitrogen atom to which they are attached, R15 and R16 form a 3 to 7-membered ring which optionally contains an additional heteroatom selected from oxygen, nitrogen or sulfur;
xe2x80x94OR15;
xe2x80x94C(O)H;
xe2x80x94CN;
xe2x80x94C(xe2x95x90O)NR5R6 in which R5 and R6 are as previously defined; alkyl, preferably lower alkyl;
aryl, preferably phenyl;
xe2x80x94C(O)OR17 in which R17 is hydrogen, alkyl containing from 1 to 7 carbon atoms, alkenyl having 3 to 7 carbon atoms, an optionally substituted aryl ring system (preferably a 6 to 10-membered aryl ring system), an optionally substituted heteroaryl ring system (preferably a 5 to 10-membered heteroaryl ring system) containing 1 or more heteroatoms, preferably 1 to 3 heteroatoms, such as oxygen, sulfur or nitrogen atoms, alkylaryl, arylalkyl, preferably benzyl, phenethyl, phenylpropyl or phenylbutyl, heteroarylalkyl, preferably furylmethyl, thienylethyl or pyridylpropyl, particularly pyridyl, phenyl, tolyl, ethylphenyl, butylphenyl or halophenyl, or a pharmaceutically acceptable cation, such as an alkali metal or alkaline earth metal, including sodium, potassium, calcium and ammonium cations;
where the optional aryl group substituents are selected from halo, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, haloalkyl and polyhaloalkyl, especially trifluoromethyl, formyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, arylalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, amino, alkylamino, dialkylamino, arylamino, alkylarylamino, alkylcarbonylamino, arylcarbonylamino, azido, nitro, mercapto, alkylthio, arylthio, perfluoroalkylthio, thiocyano, isothiocyano, alkylsulfinyl, alkylsufonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl and arylaminosulfonyl.
In certain embodiments herein, when Ar3 is 1-(3-propionyl-2-imidazolinon)yl, then R4 is other than xe2x80x94CN. Also in certain embodiments herein, when R4 is xe2x80x94C(xe2x95x90X5)xe2x80x94NR5R6, X5 is O and R5 and R6, together with the nitrogen atom to which they are attached form pyrrolidinyl, then M is other than 4-morpholinyl. In yet other certain embodiments, when M is xe2x80x94NR5R6 and R5 and R6 are methyl, then R4 is other than 1-hydroxypropyl (CH3CH2CH(OH)xe2x80x94) or ethylcarbonyl (CH3CH2C(xe2x95x90O)xe2x80x94). In still other certain embodiments, when M is 4-morpholinyl or 1-piperidinyl, then R4 is other than ethylcarbonyl (CH3CH2C(xe2x95x90O)xe2x80x94). In certain other embodiments, when M is 4-morpholinyl, than R4 is other than ethoxycarbonyl (CH3CH2OC(xe2x95x90O)xe2x80x94).
Also intended for use herein are salts of the compounds of formula (I), including salts with pharmaceutically acceptable acids and quaternary ammonium salts, N-oxides of the compounds of formula (I) and salts thereof, including salts with pharmaceutically acceptable acids and quaternary ammonium salts, including stereoisomeric forms of quaternary ammonium salts, prodrugs of the compounds of formula (I), and metabolites of the compounds of formula (I), including, for example, glucuronides.
Among the suitable quaternary ammonium salts of the compounds of formula (I), are for example, compounds of the following formulae: 
in which:
R1 is alkyl of 1 to 12 carbons which is optionally substituted with 1 to 6 halo atoms, 1 to 3 hydroxy groups or 1 to 3 alkoxy groups; alkenyl of 3 to 12 carbons which contains 1 to 3 double bonds and is optionally substituted with 1 to 6 halo atoms; alkynyl of 3 to 12 carbons which contains 1 to 3 triple bonds and is optionally substituted with 1 to 6 halo atoms; arylalkyl wherein the alkyl chain contains 1 to 6 carbons and the aryl group contains 6 to 10 carbons, preferably phenyl, and is optionally substituted with 1 to 3 aryl group substituents; arylalkenyl wherein the alkenyl chain contains 3 to 6 carbons and 1 to 3 double bonds and the aryl group contains 6 to 10 carbons, preferably phenyl, and is optionally substituted with 1 to 3 aryl group substituents; arylalkynyl where the alkynyl chain contains 3 to 6 carbons and 1 to 3 triple bonds and the aryl group contains 6 to 10 carbons, preferably phenyl, and is optionally substituted with 1 to 3 aryl group substituents; cycloalkyl of 3 to 8 carbons; cycloalkenyl of 3 to 8 carbons; cycloalkylalkyl in which the cycloalkyl group contains 3 to 8 carbons and the alkyl chain contains 1 to 6 carbons; cycloalkenylalkyl in which the cycloalkenyl group contains 3 to 8 carbons and the alkyl chain contains 1 to 6 carbons;
A is halo, hydroxy, alkoxy of 1 to 12 carbons, alkanoyloxy of 1 to 12 carbons or aroyloxy, preferably benzoyloxy, or any other pharmaceutically acceptable group that is capable of forming a counterion in a quaternary ammonium salt; and
m, X1, X2, X3, R, R2, R3, R4, R5, R6, R7, Ar1 and Ar2 are as previously defined.
It is understood that compounds of the above formula [or any of the compounds described herein] may have one or more asymmetric centers. Pure enantiomers of the above compounds may be obtained, and diastereoisomers isolated by physical separation methods, including, but not limited to crystallization and chromatographic methods. Cis and trans diasteriomeric racemates may be further resolved into their isomers. If separated, active isomers may be identified by their activity as defined herein. Such purification is not, however, necessary for preparation of the compositions or practice of the methods herein.
Of the above classes of compounds and compounds of formula (I), the compounds for use in the methods and compositions herein are those that, upon topical or local administration, exhibit activity as peripheral anti-hyperalgesics but, upon local or topical administration, are substantially devoid of CNS activity as defined below. Such compounds are typically anti-diarrheal compounds, as assessed in standard assays, that exhibit low or no activity in assays that assess CNS activity. As defined below, for purposes herein, such anti-diarrheal and CNS activity is assessed in standard assays relative to 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-4-piperidinecarboxylic acid ethyl ester (also know as 2,2-diphenyl-4-[(4-carbethoxy-4-phenyl)piperidino]butyronitrile), generically known as diphenoxylate. Selected compounds for use in the methods and compositions herein have:
(1) activity as a peripheral anti-hyperalgesic agent as assessed in any recognized in vivo or in vitro model or assay; and substantially no CNS-mediated effects, which are preferably assessed by selecting compounds that have
(2) either
(a) a B/A ratio greater than or equal to diphenoxylate and a B value at least about 2-fold greater than diphenoxylate, or
(b) a B/A ratio, at least equal to, and preferably more than about 2-fold greater than diphenoxylate, where:
B is the ED50 of the compound in an art-recognized assay [the hot plate tail withdrawal test or the tail clip test, described below, tail flick or assay that yields equivalent or substantially equivalent results] that measures CNS activity of the compound, and
A is the ED50 of the compound in an art-recognized assay [the Castor Oil test or Antagonism of PGE2-induced diarrhea in mice, described below, or an assay that yields equivalent results] that measures anti-diarrheal activity of the compound. The ratio of these activities of the compound of interest is compared to the ratio of the activities of diphenoxylate in the same assays. Among preferred compounds are those that have a B/A ratio that is more than about 3-fold greater than diphenoxylate, although compounds with a B/A ratio greater than or equal to diphenoxylate may also be used.
Preferred among the compounds of formula (I) are those of formula (II) or N-oxides thereof: 
preferably where R4 is 
and more preferably where R7 is OH, R is hydrogen or methyl, and R3 is Ar3, preferably phenyl, more preferably 4-halo-phenyl. Yet more preferred are compounds where R5 and R6 are methyl or ethyl, or together with the nitrogen to which they are attached form a pyrrolidine or piperidine ring.
More preferred among these compounds are loperamide [4-(p-chlorophenyl)-4-hydroxy-N-N-dimethyl-xcex1,xcex1-diphenyl-1-piperidinebutyramide hydrochloride] and analogs [see formula III] thereof that exhibit B/A ratios greater than loperamide [see, e.q., U.S. Pat. Nos. 3,884,916 and 3,714,159]. Such compounds include those in which:
(i) Ar1 and Ar2 are phenyl, R is hydrogen, R2 is (CH2)2, R5 and R6, with the nitrogen to which each is linked form pyrrolidine and R3 is 4-chlorophenyl or 3,4,-di-chlorophenyl;
(ii) Ar1 and Ar2 are phenyl, R is hydrogen, R2 is (CH2)2, R5 and R6, with the nitrogen to which each is linked form piperidinyl and R3 is phenyl;
(iii) Ar1 and Ar2 are phenyl, R2 is (CH2)2, R is hydrogen, R5 and R6 are each methyl and R3 is 4-bromophenyl;
(iv) Ar1 and Ar2 are phenyl, R2 is (CH2)2, R is hydrogen, R5 and R6 are methyl and ethyl, respectively, and R3 is 4-chlorophenyl;
(v) Ar1 and Ar2 are phenyl, R2 is CH2CHCH3, R is hydrogen, R5 and R6 are each methyl and R3 is 4-fluorophenyl; and
(vi) Ar1 and Ar2 are phenyl, R2 is CH2CH2, R is 4-methyl, R5 and R6 are each methyl and R3 is 3-trifluoromethylphenyl or phenyl.
In certain other preferred embodiments, the compounds of formula (I) are those of formula (II) above, preferably where R4 is cyano and R7 is xe2x80x94C(O)OR17, in which R17 is preferably hydrogen or lower alkyl, more preferably methyl or ethyl. More preferred among these compounds is diphenoxylate (2,2-diphenyl-4-[(4-carbethoxy-4-phenyl)piperidino]butyronitrile) and defenoxine (1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-4-piperidinecarboxylic acid).
Because of its ready availability and demonstrated safety, loperamide HCl is presently most preferred.
Compositions formulated for topical and local administration for treatment and/or prevention of hyperalgesia are also provided. The compositions provided herein, may be formulated for single or multiple dosage administration, and contain an anti-hyperalgesic effective amount (where the amount refers that which is delivered as a single dose) of one or more of the selected compounds in a vehicle formulated for topical or local administration. Generally the compounds are provided in the form of a suspension or emulsion at concentrations of from about 0.1%, preferably from greater than about 1%, particularly when formulated in aqueous medium for application to the nasal passages or lungs, up to 50% or more.
The compositions are formulated as creams, aqueous or non-aqueous suspensions, lotions, emulsions, suspensions or emulsions containing micronized particles, gels, foams, aerosols, solids and other suitable vehicles for application to the skin, eyes, lips and mucosa, as suppositories or creams for vaginal administration, and as combinations with bandages, patches, bioadhesives and dressings. The compounds may be formulated in combination with other agents, such as local anesthetics, vasoconstrictors and other therapeutic agents. The other agents may be mixed in the compositions or provided separately and administered prior to, simultaneously with or subsequent to administration of the compositions provided for the methods herein. Such agents include, but are not limited to: antibiotics, including cephalosporins, xcex2-lactams, tetracyclines, vancomycins, sulfas and aminoglycosides; antivirals, including acylovir; antifungals including clotrimazole; vasoconstrictors; non-steroidal anti-inflammatories (NSAls) and steroids.
Methods of treating and/or preventing hyperalgesia by applying an amount of the compositions provided herein effective to ameliorate or eliminate the hyperalgesic state are provided. Thus, methods of treating and/or preventing pain and irritation associated with inflammation following local infection, blisters, boils, or acute skin injuries, such as abrasions, burns, superficial cuts, surgical incisions, toothaches, contusions, irritations, inflammatory skin conditions, including but not limited to poison ivy, and allergic rashes and dermatitis and any condition that yields a hyperalgesic pain state and other such conditions are provided.
Articles of manufacture containing: packaging material, a compound [or compounds] provided herein, which is effective for ameliorating peripheral hyperalgesia within the packaging material, and a label that indicates that the compound, acid, salt or other derivative thereof is used for treating and/or preventing hyperalgesic conditions, are provided.